Table 2.
Pharmacokinetic parameter estimates for substrates of CYP1A2 (caffeine), CYP2C19 (omeprazole), and CYP3A (midazolam) and their metabolites (paraxanthine, 5-HO, and 1ʹ-HM, respectively) in the presence and absence of adavosertib 225 mg bid (pharmacokinetic analysis set)
| Point estimates of the geometric LS mean ratios S + AD/S, % (90% CI) | Median tmax, h (range) | Mean t½ h (SD) | Mean CL/F, L/h (SD) | Mean Vz/F, L (SD) | Mean MR | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| AUC | AUC0–t | Cmax | |||||||||||||||
| AUC, ng·h/mL |
AUC0–t, ng·h/mL |
Cmax, ng/mL |
− AD | + AD | − AD | + AD | − AD | + AD | − AD | + AD | − AD | + AD | − AD | + AD | − AD | + AD | |
| Caffeinea |
149.1 (131.3–169.3) |
160.8 (143.3–180.5) |
103.8 (92.2–116.9) |
0.5 (0.3–3.0) |
0.7 (0.3–3.0) |
6.4 (3.8) |
13.5 (6.8) |
5.7 (2.5) |
3.8 (1.9) |
39.3 (15.0) |
37.9 (12.1) |
NA | |||||
| Omeprazole |
180.2 (145.7–222.9) |
198.1 (160.3–244.7) |
145.5 (114.0–185.7) |
3.0 (0.7–6.0) |
3.9 (0.5–8.0) |
2.0 (1.0) |
2.5 (1.3) |
13.3 (10.5) |
7.6 (7.3) |
28.3 (16.6) |
19.8 (10.1) |
NA | |||||
| Midazolam |
155.3 (138.6–173.9) |
155.2 (140.5–171.5) |
138.5 (118.9–161.3) |
0.5 (0.2–1.0) |
0.5 (0.2–1.0) |
5.5 (2.6) |
6.6 (3.0) |
59.0 (34.3) |
39.7 (14.5) |
409.9 (211.5) |
364.1 (182.7) |
NA | |||||
| Paraxanthineb | NC | NC |
81.2 (74.6–88.5) |
8.0 (4.0–11.8) |
9.9 (6.0–24.9) |
7.0 (2.7) |
12.2 (5.4) |
NA | 0.65 | NC | 0.54 | 0.32 | 0.23 | 0.16 | |||
| 5-HO |
143.0 (123.8–165.0) |
148.8 (129.6–170.8) |
92.9 (78.6–109.8) |
3.0 (0.7–6.0) |
4.0 (1.8–7.8) |
2.7 (1.7) |
4.5 (4.7) |
NA | 0.50 | 0.46 | 0.73 | 0.50 | 0.53 | 0.30 | |||
| 1ʹ-HM |
153.5 (131.0–179.8) |
158.2 (139.1–180.0) |
133.4 (106.5–167.1) |
0.5 (0.3–2.1) |
0.5 (0.2–1.0) |
7.2 (6.1) |
7.6 (7.1) |
NA | 0.41 | 0.45 | 0.43 | 0.44 | 0.47 | 0.43 | |||
Patient numbers for cocktail without AD (period 1) were: caffeine (AUC: 22; AUC0–t, Cmax, tmax, and t½: 25), omeprazole (AUC and t½: 21; AUC0–t, Cmax, and tmax: 27), midazolam (AUC and t½: 22; AUC0–t, Cmax, and tmax: 23), paraxanthine (AUC: 10; t½: 14; AUC0–t, Cmax, and tmax: 19), 5-HO (AUC: 22; t½: 24; AUC0–t, Cmax, and tmax: 28), and 1'-HM (AUC: 20; t½: 22; AUC0–t, Cmax, and tmax: 24). Patient numbers for cocktail with AD (period 2) were: caffeine (AUC: 8; AUC0–t and t½: 18; Cmax and tmax: 19), omeprazole (AUC and t½: 15; AUC0–t: 18; Cmax and tmax: 20), midazolam (AUC and t½: 18; AUC0–t, Cmax, and tmax: 19), paraxanthine (AUC: 1; t½: 5; AUC0–t: 15; Cmax and tmax: 16), 5-HO (AUC: 13; t½: 17; AUC0–t: 18; Cmax and tmax: 20), and 1'-HM (AUC: 17; t½: 18; AUC0–t, Cmax and tmax: 19). aCaffeine AUC was only reliably characterized in eight patients receiving cocktail with AD in period 2. Caffeine AUC increased in all seven patients with paired data for both periods; results were considered representative of the data. bParaxanthine AUC was only reliably characterized in 10 patients in period 1 (cocktail only) and one patient in period 2 (cocktail + AD); thus, the treatment comparison for AUC was not considered scientifically meaningful. 1ʹ-HM 1ʹ-hydroxymidazolam, 5-HO 5-hydroxyomeprazole, AD adavosertib, AUC area under the plasma concentration–time curve, AUC0–t area under the plasma concentration–time curve from time zero to time of the last quantifiable concentration, CI confidence interval, CL/F apparent clearance, Cmax maximum plasma drug concentration, CYP cytochrome P450, LS least-squares, MR metabolic ratio in relation to parent compound, NA not available, NC not calculable, S + AD/S substrate (or compound) + adavosertib compared with substrate or compound alone, SD standard deviation, t½ plasma terminal half-life, tmax time to reach maximum plasma concentration, Vz/F apparent volume of distribution